Article ; Online: Upregulation of TRPM7 channels by angiotensin II triggers phenotypic switching of vascular smooth muscle cells of ascending aorta.
2012 Volume 111, Issue 9, Page(s) 1137–1146
Abstract: Rationale: Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs ... was activated in Ang II-infused ascending aorta. Knockdown of TRPM7 with small interfering RNA ... that upregulation of TRPM7 channels by Ang II contributes to the development of the proliferative phenotype ...
| Abstract | Rationale: Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs). It has been demonstrated to promote the proliferative phenotype of VSMCs in mouse ascending aorta, but the underlying mechanisms remain incompletely understood. Objective: The present study was designed to explore whether the Ca(2+)-permeable transient receptor potential melastatin 7 (TRPM7) channel is involved in Ang II-induced phenotype switching of ascending aortic VSMCs and to dissect the molecular mechanisms by which TRPM7 modulates VSMC phenotype. Methods and results: As revealed by current recording, Ang II infusion increased TRPM7 whole-cell currents in ascending aortic VSMCs. The increase in TRPM7 currents was found to result from enhanced expression of TRPM7 protein rather than elevated single-channel activity (open probability and slope conductance) and/or reduced Mg(2+)-mediated channel block. Mechanistically, Ang II elevated TRPM7 expression via Ang II type 1 receptor-mediated ERK1/2 signaling. As indicated by the expression levels of VSMC differentiation marker genes, phenotypic switching of ascending aorta occurred during Ang II infusion. Meanwhile, ERK1/2-Elk-1 signaling pathway known to suppress VSMC differentiation was activated in Ang II-infused ascending aorta. Knockdown of TRPM7 with small interfering RNA established a causative role of TRPM7 in Ang II-induced phenotypic change and promotion of cell proliferation. Moreover, TRPM7 was shown to be required for Pyk2-ERK1/2-Elk-1 pathway activation by Ang II, which potentiated TRPM7 channel function and thus activated the Ca(2+)-sensitive kinase Pyk2. Finally, TRPM7 knockdown attenuated Ang II-induced displacement of myocardin from SM22 promoter, but the effects could be reversed by expression of constitutively active c-Src. Conclusions: Our data establish that upregulation of TRPM7 channels by Ang II contributes to the development of the proliferative phenotype of ascending aortic VSMCs, and TRPM7 channel suppresses VSMC gene expression via Ca(2+) influx-mediated activation of Pyk2-ERK1/2-Elk-1 pathway. |
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| MeSH term(s) | Angiotensin II/pharmacology ; Animals ; Aorta/cytology ; Aorta/drug effects ; Cell Differentiation/drug effects ; Cell Differentiation/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Focal Adhesion Kinase 2/drug effects ; Focal Adhesion Kinase 2/physiology ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Phenotype ; Signal Transduction/drug effects ; Signal Transduction/physiology ; TRPM Cation Channels/metabolism ; Up-Regulation/drug effects ; Up-Regulation/physiology ; ets-Domain Protein Elk-1/drug effects ; ets-Domain Protein Elk-1/physiology | ||||||||||
| Chemical Substances | Elk1 protein, mouse ; TRPM Cation Channels ; ets-Domain Protein Elk-1 ; Angiotensin II (11128-99-7) ; Trpm7 protein, mouse (EC 2.7.1.-) ; Focal Adhesion Kinase 2 (EC 2.7.10.2) ; Ptk2b protein, mouse (EC 2.7.10.2) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2012-10-12 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 80100-8 | ||||||||||
| ISSN | 1524-4571 ; 0009-7330 ; 0931-6876 | ||||||||||
| ISSN (online) | 1524-4571 | ||||||||||
| ISSN | 0009-7330 ; 0931-6876 | ||||||||||
| DOI | 10.1161/CIRCRESAHA.112.273755 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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